U.S. patent application number 12/502708 was filed with the patent office on 2010-01-21 for biocompatible polymeric compound, biocompatible polymer and polymer particles.
This patent application is currently assigned to FUJIFILM Corporation. Invention is credited to Kazuhiro Aikawa, Kazuya Takeuchi, Takashi TAMURA, Masahiko Taniguchi.
Application Number | 20100016534 12/502708 |
Document ID | / |
Family ID | 41530872 |
Filed Date | 2010-01-21 |
United States Patent
Application |
20100016534 |
Kind Code |
A1 |
TAMURA; Takashi ; et
al. |
January 21, 2010 |
BIOCOMPATIBLE POLYMERIC COMPOUND, BIOCOMPATIBLE POLYMER AND POLYMER
PARTICLES
Abstract
The compound represented by general formula (I) below:
##STR00001## wherein R.sup.10 represents hydrogen atom or methyl
group; X represents --O(C.dbd.O)-- or the like; and R represents
hydrogen atom, a substituted or unsubstituted alkyl group, a
substituted or unsubstituted aryl group, or the like, and a polymer
obtained by polymerizing a polymeric compound comprising the
compound, which are useful for manufacturing hydrophilic polymer
materials of high biocompatibility.
Inventors: |
TAMURA; Takashi; (Kanagawa,
JP) ; Takeuchi; Kazuya; (Kanagawa, JP) ;
Taniguchi; Masahiko; (Kanagawa, JP) ; Aikawa;
Kazuhiro; (Kanagawa, JP) |
Correspondence
Address: |
YOUNG & THOMPSON
209 Madison Street, Suite 500
Alexandria
VA
22314
US
|
Assignee: |
FUJIFILM Corporation
Tokyo
JP
|
Family ID: |
41530872 |
Appl. No.: |
12/502708 |
Filed: |
July 14, 2009 |
Current U.S.
Class: |
526/274 ;
558/169 |
Current CPC
Class: |
C07F 9/59 20130101; C07F
9/091 20130101; C08F 30/02 20130101 |
Class at
Publication: |
526/274 ;
558/169 |
International
Class: |
C08F 30/02 20060101
C08F030/02; C07F 9/09 20060101 C07F009/09 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 15, 2008 |
JP |
2008-183441 |
Claims
1. A compound represented by general formula (I) below:
##STR00015## wherein R.sup.10 represents hydrogen atom or methyl
group; X represents --O--, --S--, --NR.sup.2--, or --O(C.dbd.O)--;
R.sup.2 represents hydrogen atom, a substituted or unsubstituted
alkyl group, or a substituted or unsubstituted aryl group; and R
represents hydrogen atom, a substituted or unsubstituted alkyl
group, a substituted or unsubstituted alkenyl group, a substituted
or unsubstituted cycloalkyl group, a substituted or unsubstituted
cycloalkenyl group, a substituted or unsubstituted heterocyclic
group, or a substituted or unsubstituted aryl group.
2. The compound according to claim 1, wherein X is
--O(C.dbd.O)--.
3. The compound according to claim 1, wherein R is a substituted or
unsubstituted alkyl group.
4. The compound according to claim 3, wherein R is a C1 to C20
unsubstituted alkyl group.
5. The compound according to claim 1, wherein R is a substituted or
unsubstituted aryl group.
6. The compound according to claim 5, wherein R comprises two or
more iodine atoms.
7. The compound according to claim 5, wherein R is an
iodine-substituted phenyl group comprising two or more iodine
atoms, with the iodine-substituted phenyl group being optionally
substituted with a substituent selected from the group consisting
of amino group, carboxyl group, a halogen atom,
--NR.sup.3(C.dbd.O)R.sup.4, --(C.dbd.O)OR.sup.5,
--(C.dbd.O)NR.sup.6R.sup.7 (with each of R.sup.3 to R.sup.7
representing hydrogen atom, a substituted or unsubstituted alkyl
group, or a substituted or unsubstituted aryl group), a substituted
or unsubstituted alkyl group, and a substituted or unsubstituted
aryl group.
8. The compound according to claim 7, wherein R is an
iodine-substituted phenyl group substituted with three iodine
atoms.
9. A polymer obtained by polymerization reaction of a composition
comprising the compound according to claim 1.
10. The polymer according to claim 9 comprising the structural unit
represented by general formula (11) below: ##STR00016## wherein
R.sup.11 represents hydrogen atom or methyl group, and R.sup.1
represents hydrogen atom or a substituted or unsubstituted alkyl
group.
11. The polymer according to claim 9 comprising the structural unit
represented by general formula (12) below: ##STR00017## wherein
R.sup.12 represents hydrogen atom or methyl group; Phe represents
an iodine-substituted phenyl group comprising two or more iodine
atoms, with the iodine-substituted phenyl group being optionally
substituted with a substituent selected from the group consisting
of amino group, carboxyl group, a halogen atom,
--NR.sup.3(C.dbd.O)R.sup.4, --(C.dbd.O)OR.sup.5,
--(C.dbd.O)NR.sup.6R.sup.7 (with each of R.sup.3 to R.sup.7
representing hydrogen atom a substituted or unsubstituted alkyl
group, or a substituted or unsubstituted aryl group), a substituted
or unsubstituted alkyl group, and a substituted or unsubstituted
aryl group.
12. The polymer according to claim 9 comprising the structural unit
represented by general formula (11) and the unit structure
represented by general formula (12) below: ##STR00018## wherein
each of R.sup.11 and R.sup.12 independently represents hydrogen
atom or methyl group; R.sup.1 represents hydrogen atom or a
substituted or unsubstituted alkyl group; and Phe represents an
iodine-substituted phenyl group comprising two or more iodine
atoms, with the iodine-substituted phenyl group being optionally
substituted with a substituent selected from the group consisting
of amino group, carboxyl group, a halogen atom,
--NR.sup.3(C.dbd.O)R.sup.4, --(C.dbd.O)OR.sup.5,
--(C.dbd.O)NR.sup.6R.sup.7 (with each of R.sup.3 to R.sup.7
representing a hydrogen atom, a substituted or unsubstituted alkyl
group, or a substituted or unsubstituted aryl group), a substituted
or unsubstituted alkyl group, and a substituted or unsubstituted
aryl group.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of priority under 35 USC 119
to Japanese Patent Application No. 2008-183441 filed on Jul. 15,
2008, the disclosure of which is expressly incorporated by
reference herein in its entirety.
TECHNICAL FIELD
[0002] The present invention relates to polymeric compounds. More
particularly, the present invention relates to a new polymeric
compound, having surfactant properties combining both hydrophilic
and hydrophobic groups, that is useful for manufacturing
hydrophilic polymer materials of high biocompatibility. The present
invention further relates to polymers obtained by polymerizing the
aforementioned compounds, and to particles of minute particle
diameter containing the polymers.
BACKGROUND ART
[0003] In recent years, materials comprised chiefly of hydrophilic
polymers have been widely employed in artificial organs, artificial
muscle, medicinal drug carriers, cellular scaffolding materials,
agricultural materials (moisture-retaining agents), and the
like.
[0004] Examples of natural hydrophilic polymers include alginates,
collagen, hyaluronic acid, chondroitin sulfate, fibrin, chitosan,
and silk. These polymers are of high biocompatibility, but present
problems in the form of high biodegradability and low mechanical
strength. Contamination by pathogens is also a concern.
[0005] Examples of artificially synthesized hydrophilic polymers
include polyethylene glycol, polysodium acrylate, polyacrylamide,
polylactic acid, polyhydroxyethyl methacrylate, and
polyacrylamidomethylpropane sulfuric acid. These polymers are of
high mechanical strength and present little risk of contamination
by pathogens. However, they present a problem in the form of low
biocompatibility. There is also a problem in that some of these
polymers are highly toxic.
[0006] In recent years, a polymer material that is highly
biocompatible and hydrophilic has been provided by employing
2-methacryloyloxyethyl phosphorylcholine (MPC) (Collected Papers on
Polymers, 1978, Vol. 35, No. 7, pp. 423-427; and Japanese Patent
No. 2870727, the disclosures of which are expressly incorporated by
reference herein in their entireties). The phosphatidyl choline
moiety in polymers manufactured with MPC has a structure similar to
that of phospholipids, which are compounds found within the body.
The fact that this moiety is charge neutral and highly hydrophilic
is a factor that increases its biocompatibility.
[0007] However, the high solubility in water of
2-methacryloyloxyethyl phosphorylcholine complicates synthesis.
Polymers comprising a high ratio of 2-methacryloyloxyethyl
phosphorylcholine present problems in that they are too hydrophilic
to form particles in water, and have low mechanical strength.
[0008] Recently, drug delivery technology has been employed to
selectively accumulate imaging agents in affected areas in an
attempt to heighten the contrast of images of affected areas and
reduce the quantity of imaging agent administered.
[0009] For example, the encasing of a drug or the like in the form
of an imaging agent within a particle such as a liposome or micelle
and the modification of the surface of the particle with a ligand
molecule or the like, and the coating of drugs with polymers, have
been reported (U.S. Pat. Nos. 5,686,061 and 5,019,370;
International Patent Application Publication No. 06106513; U.S.
Patent Application Publication Nos. 2007098640, 2007098641, and
2007098642; J. Am. Chem. Soc. 2000, 122, 8940-8945; J. Control.
Release 2007, 122, 269-277; and Nature Medicine 2007, 13, 636-641,
the disclosures of which are expressly incorporated by reference
herein in their entireties). However, such imaging agents have low
stability and low safety, and large particle size, and tend to be
captured by the reticuloendothelial system, and the like, thereby
compromising imaging performance.
[0010] Iodine-containing compounds, for example, are known X-ray
imaging agents. Triiode benzenes are employed in vascular imaging
and urethrography. However, most X-ray imaging agents are
water-soluble compounds of low molecular weight, and do not remain
in the blood long following administration. Thus, imaging must be
conducted immediately after administering the imaging agent.
Toxicity when a large quantity of imaging agent is employed is
frequently reported (Toxicology 2005, 209, 185-187, the disclosure
of which is expressly incorporated by reference herein in its
entirety).
DISCLOSURE OF THE INVENTION
[0011] The object of the present invention is to provide a new
polymeric compound that is useful for manufacturing hydrophilic
polymer materials of high biocompatibility. A further object of the
present invention is to provide a polymer that is manufactured by
polymerizing such a polymeric compound.
[0012] The present inventors conducted extensive research into
achieving the above objects, resulting in the discovery of a new
polymeric compound suited to the manufacturing of polymers similar
to highly biocompatible phospholipids. The present invention was
achieved on the basis of these findings.
[0013] The present invention thus provides [1] to [12] below:
[0014] [1] A compound represented by general formula (I) below:
##STR00002##
[0014] wherein R.sup.10 represents hydrogen atom or methyl group; X
represents --O--, --S--, --NR.sup.2--, or --O(C.dbd.O)--; R.sup.2
represents hydrogen atom, a substituted or unsubstituted alkyl
group, or a substituted or unsubstituted aryl group; and R
represents hydrogen atom, a substituted or unsubstituted alkyl
group, a substituted or unsubstituted alkenyl group, a substituted
or unsubstituted cycloalkyl group, a substituted or unsubstituted
cycloalkenyl group, a substituted or unsubstituted heterocyclic
group, or a substituted or unsubstituted aryl group. [0015] [2] The
compound according to [1], wherein X is --O(C.dbd.O)--. [0016] [3]
The compound according to [1] or [2], wherein R is a substituted or
unsubstituted alkyl group. [0017] [4] The compound according to
[3], wherein R is a C1 to C20 unsubstituted alkyl group. [0018] [5]
The compound according to [1] or [2], wherein R is a substituted or
unsubstituted aryl group. [0019] [6] The compound according to [5],
wherein R comprises two or more iodine atoms. [0020] [7] The
compound according to [5], wherein R is an iodine-substituted
phenyl group comprising two or more iodine atoms, with the
iodine-substituted phenyl group being optionally substituted with a
substituent selected from the group consisting of amino group,
carboxyl group, a halogen atom, --NR.sup.3(C.dbd.O)R.sup.4,
--(C.dbd.O)OR.sup.5, --(C.dbd.O)NR.sup.6R.sup.7 (with each of
R.sup.3 to R.sup.7 representing hydrogen atom, a substituted or
unsubstituted alkyl group, or a substituted or unsubstituted aryl
group), a substituted or unsubstituted alkyl group, and a
substituted or unsubstituted aryl group. [0021] [8] The compound
according to [7], wherein R is an iodine-substituted phenyl group
substituted with three iodine atoms. [0022] [9] A polymer obtained
by polymerization reaction of a composition comprising the compound
according to any one of [1] to [8]. [0023] [10] A polymer
comprising the structural unit represented by general formula (11)
below:
##STR00003##
[0023] wherein R.sup.11 represents hydrogen atom or methyl group,
and R.sup.1 represents hydrogen atom or a substituted or
unsubstituted alkyl group. [0024] [11] A polymer comprising the
structural unit represented by general formula (12) below:
##STR00004##
[0024] wherein R.sup.12 represents hydrogen atom or methyl group;
Phe represents an iodine-substituted phenyl group comprising two or
more iodine atoms, with the iodine-substituted phenyl group being
optionally substituted with a substituent selected from the group
consisting of amino group, carboxyl group, a halogen atom,
--NR.sup.3(C.dbd.O)R.sup.4, --(C.dbd.O)OR.sup.5,
--(C.dbd.O)NR.sup.6R.sup.7 (with each of R.sup.3 to R.sup.7
representing hydrogen atom, a substituted or unsubstituted alkyl
group, or a substituted or unsubstituted aryl group), a substituted
or unsubstituted alkyl group, and a substituted or unsubstituted
aryl group. [0025] [12] A polymer comprising the structural unit
represented by general formula (11) and the unit structure
represented by general formula (12) below:
##STR00005##
[0025] wherein each of R.sup.11 and R.sup.12 independently
represents hydrogen atom or methyl group; R.sup.1 represents
hydrogen atom or a substituted or unsubstituted alkyl group; and
Phe represents an iodine-substituted phenyl group comprising two or
more iodine atoms, with the iodine substituted phenyl group being
optionally substituted with a substituent selected from the group
consisting of amino group, carboxyl group, a halogen atom,
--NR.sup.3(C.dbd.O)R.sup.4, --(C.dbd.O)OR.sup.5,
--(C.dbd.O)NR.sup.6R.sup.7 (with each of R.sup.3 to R.sup.7
representing a hydrogen atom, a substituted or unsubstituted alkyl
group, or a substituted or unsubstituted aryl group), a substituted
or unsubstituted alkyl group, and a substituted or unsubstituted
aryl group.
BEST MODE OF CARRYING OUT THE INVENTION
[0026] The present invention will be described in detail below.
[0027] Ranges that are given in the present specification and
consist of two numbers separated by the word "to" are intended to
include the numbers as lower and upper limits, respectively.
[0028] When the descriptive phrasing "substituted or unsubstituted"
or "optionally substituted" is employed for a given group in the
present specification, the phrasing means that the group may be
substituted with one or more groups. However, the number,
substitution position, and type of bonded substituent are not
specifically limited unless specifically stated. When two or more
substituents are present in a given group, the substituents may be
identical or different. When a given group has a substituent in the
present specification, examples of the substituent include a
halogen atom (in the present specification, a "halogen atom" means
a fluorine atom, chlorine atom, bromine atom, or iodine atom); an
alkyl group (in the present specification, an "alkyl group" means
an alkyl group that is linear, branched, or some combination
thereof; a cycloalkyl group; an alkenyl group (in the present
specification, an "alkenyl group" means an alkenyl group that is
linear, branched, or some combination thereof; a cycloalkenyl
group; an alkynyl group; an aryl group; a heterocyclic group; cyano
group; hydroxyl groups; nitro group; a carboxyl group; a carbamoyl
group; an alkoxy group; an aryloxy group; a heterocyclic oxy group;
an acyloxy group; a carbamoyloxy group; a carbonyloxy group; an
amino group (including an anilino group); a carbonylamino group; an
acyl group; an aryloxycarbonyl group; an alkoxycarbonyl group; a
carbamoyl group; an aryl or heterocyclic azo group; an imido group;
a substituent in the form of any one of the above substituents that
is substituted with any one or more of the above substituents; and
a substituent in the form of any one of the above substituents,
that has been substituted with any one of the above substituents,
that has itself been further substituted with any one or more of
the above substituents.
[0029] In general formula (I), R.sup.10 represents hydrogen atom or
methyl group. Although not a specific limitation, R.sup.10 is
preferably methyl group. The same holds true for R.sup.11 in
general formula (11) and R.sup.12 in general formula (12).
[0030] In general formula (I), X represents --O--, --S--,
--NR.sup.2--, or --O(C.dbd.O)-- (with R.sup.2 representing hydrogen
atom, a substituted or unsubstituted alkyl group, or a substituted
or unsubstituted aryl group). X preferably represents --O--,
--NH--, or --O(C.dbd.O)--, and more preferably represents
--O(C.dbd.O)--.
[0031] The total number of carbon atoms in an unsubstituted alkyl
group represented by R or R.sup.1 is preferably 1 to 30, more
preferably 1 to 20. Examples of alkyl groups represented by R or
R.sup.1 include methyl group, ethyl group, propyl group, i-propyl
group, butyl group, s-butyl group, t-butyl group, hexyl group,
octyl group, 2-ethylhexyl group, decyl group, undecyl group,
dodecyl group, tridecyl group, tetradecyl group, pentadecyl group,
hexadecyl group, and heptadecyl group.
[0032] R or R.sup.1 may represent a substituted alkyl group in the
form of the above alkyl group having one or more substituents.
Examples of such substituted alkyl groups include chlorobutyl
group, benzyl group, 2-ethynylpropyl group, phenylethyl group,
cyanopropyl group, methoxyethyl group, hydroxymethyl group,
aminomethyl group, chlorodecyl group, ethynylhexadecyl group,
phenylundecyl group, cyanooctyl group, methoxypentadecyl group,
hydroxytetradecyl group, aminotridecyl group,
1-methoxycarbamoylethyl group,
1(-N-(2-phenyl-1-carboxy)ethylcarbamoyl)ethyl group, and
2-ethoxycarbonylbutyl groups. Examples of the substituted alkyl
groups further include the compounds incorporating phenyl groups in
the examples of the above substituted alkyl group, wherein the
phenyl groups are each substituted with 2 or more, preferably 3 or
more, iodine atoms. The total number of carbon atoms of the
substituted alkyl group is preferably 2 to 40, more preferably 2 to
25.
[0033] Neither the position nor number of double bonds in an
unsubstituted alkenyl group represented by R is specifically
limited. The double bond may be of E or Z configuration. When
multiple double bonds are present, there may be a mixture of E and
Z configurations. The total number of carbon atoms of an alkenyl
group represented by R is preferably 2 to 30, more preferably 5 to
20. Examples of unsubstituted alkenyl groups include vinyl group,
1-propenyl group, 2-propenyl group, 3-butenyl group, pentenyl
group, 2-hexenyl group, hexadienyl group, 5-dodecenyl group,
10-pentadecenyl group, 14-hexadecenyl group, and 9-heptadecenyl
group. R may represent a substituted alkenyl group in the form of
the above unsubstituted alkenyl group having one or more
substituents.
[0034] The total number of carbon atoms of an unsubstituted
cycloalkyl group represented by R is preferably 3 to 20, more
preferably 5 to 10. Examples of unsubstituted cycloalkyl groups
include cyclopropyl group, cyclobutyl group, cyclopentyl group,
cyclohexyl group, and cycloheptyl groups. R may represent a
substituted cycloalkyl group in the form of the above unsubstituted
cycloalkyl group having one or more substituents. The total number
of carbon atoms of a cycloalkenyl group represented by R is
preferably 4 to 20, more preferably 5 to 10. An example of an
unsubstituted cycloalkenyl group includes a cyclohexenyl group R
may represent a substituted cycloalkenyl group in the form of the
above unsubstituted cycloalkenyl group having one or more
substituents.
[0035] An unsubstituted heterocyclic group represented by R may be
a saturated or unsaturated aliphatic heterocyclic group or aromatic
heterocyclic group. The hetero atoms in the heterocyclic group are
not specifically limited, with one or more atoms selected from
among oxygen atom, sulfur atom, and nitrogen atom being desirable.
Examples of heterocyclic groups include cyclic groups derived from
furan, dihydrofuran, tetrahydrofuran, pyran, dihydropyran,
tetrahydropyran, benzofuran, dihydrobenzofuran, isobenzofuran,
chromene, chroman, isochroman, thiophene, benzothiophene, pyrrole,
pyrroline, pyrrolidine, imidazole, imidazoline, imidazolidine,
pyrazole, pyrazoline, pyrazolidine, triazole, tetrazole, pyridine,
pyridine oxide, piperidine, pyrazine, piperazine, pyrimidine,
pyridazine, indole, indoline, isoindole, isoindoline, indazole,
benzoimidazole, benzotriazole, tetrahydroisoquinoline,
benzothiazolinone, benzoxazolinone, purine, quinolidine, quinoline,
phthalazine, naphthyridine, quinoxaline, quinozoline, cinnoline,
pteridine, oxazole, oxazolidine, isoxazole, isoxazolidine,
oxadiazol, thiazol, benzothiazol, thiadiridine, isothiazol,
isothiazolidine, benzodioxol, dioxane, benzodioxane, dithiane,
morpholine, thiomorpholine, phthalimide, homopiperidinyl,
homopiperazinyl, and the like. The bonding position on the ring is
not limited. R may represent a substituted heterocyclic group in
the form of the above unsubstituted heterocyclic group having one
or more substituents.
[0036] The total carbon number of an unsubstituted aryl group
represented by R or any of R.sup.1 to R.sup.7 is preferably 6 to
30, more preferably 6 to 20. Examples of such aryl groups include
phenyl group, naphthyl group, and anthracenyl group. R or any of
R.sup.1 to R.sup.7 may represent a substituted aryl group in the
form of the above unsubstituted aryl group having one or more
substituents. Examples of substituted aryl groups include
methoxyphenyl group, chlorophenyl group, hydroxyphenyl group,
aminophenyl group, ethylphenyl group, biphenyl group, nonylphenyl
group, octylphenyl group, fluorophenyl group, and iodophenyl
group.
[0037] A substituted aryl group represented by R is preferably an
iodine-substituted phenyl group including two or more iodine atoms.
The number of iodine atoms in the iodine-substituted phenyl group
is preferably three. Such an iodine substituted phenyl group may
have in addition to iodine other one or more substituents selected
from among amino group, carboxyl group, a halogen atom,
--NR.sup.3(C.dbd.O)R.sup.4, --(C.dbd.O)OR.sup.5,
--(C.dbd.O)NR.sup.6R.sup.7 (wherein each of R.sup.3 to R.sup.7
represents hydrogen atom, a substituted or unsubstituted alkyl
group, or a substituted or unsubstituted aryl group), a substituted
or unsubstituted alkyl group, and a substituted or unsubstituted
aryl group.
[0038] The number of carbon atoms of an unsubstituted alkyl group
represented by any of R.sup.2 to R.sup.7 or the unsubstituted alkyl
group substituent on a substituted aryl group represented by R is
preferably 1 to 20, more preferably 1 to 6. The substituent in a
substituted aryl group represented by R, or any of R.sup.3 to
R.sup.7, may be a substituted alkyl group.
[0039] When the compound represented by general formula (I) is an
aryl group, preferably comprising a phenyl group, the aryl group
preferably have a substituent in the form of iodine. Preferably two
or more iodine atoms, more preferably three iodine atoms, are
substituted. Such a compound represented by general formula (I), or
a polymer obtained by polymerizing such a compound, can be
administered into the body and employed as an X-ray imaging
agent.
[0040] The following compounds are specific examples of the
compound represented by general formula (I):
##STR00006## ##STR00007## ##STR00008## ##STR00009## ##STR00010##
##STR00011## ##STR00012##
[0041] The compound represented by general formula (I) can
generally be manufactured as set forth below.
[0042] Glycidyl(meth)acrylate and a carboxylic acid are added to a
reaction solvent (an alcohol, acetone, methyl ethyl ketone,
cyclohexanone, dimethyl acetamide, dimethyl formamide, dimethyl
sulfoxide, sulfolane, N-methylpyrrolidone, or the like). As needed,
a catalyst (an ammonium salt such as tetrabutylammonium bromide) is
added, and the mixture is reacted with heating to 50.degree. C. or
higher but not greater than 120.degree. C. to produce an
intermediate.
[0043] Following the reaction, processing can be suitably conducted
by methods known to persons having ordinary skill in the art, such
as the methods given in the examples.
[0044] The intermediate can be reacted with
2-chloro-2-oxo-1,3,2-dioxaphospholane to obtain the compound
represented by general formula (I). This reaction can be suitably
conducted, for example, by the method set forth in the examples. A
temperature of -70.degree. C. or higher, but not higher than
0.degree. C., suffices during the reaction. A reaction solvent in
the form of methylene chloride, chloroform, acetone,
tetrahydrofuran, diethyl ether, 1,2-dichloroethane, chlorobenzene,
or the like can be suitably selected.
[0045] The compound represented by general formula (I) can be
polymerized, for example, by charging a solvent and the compound
represented by general formula (I) to a reaction vessel and
suitably heating them in the presence of a polymerization
initiator. In copolymerization, it suffices for both of the monomer
compounds being copolymerized to be present in the above
solution.
[0046] The only requirement of the solvent employed in
polymerization is that it be capable of dissolving the compound
represented by general formula (I), and as needed, the monomers
being copolymerized and a polymerization initiator. Examples of
solvents include water, methanol, ethanol, propanol, butanol,
tetrahydrofuran, acetonitrile, acetone, benzene, toluene,
dimethylformamide, and mixtures thereof.
[0047] The polymerization initiator employed in polymerization is
not specifically limited. However, a radical polymerization
initiator is preferable. Examples of radical polymerization
initiators include aliphatic azo compounds such as
2'-azobisisobutyronitrile and azobismalenonitrile, and organic
peroxides such as benzoyl peroxide, lauroyl peroxide, ammonium
peroxide, and potassium peroxide.
[0048] In polymerization, two or more compounds represented by
general formula (I) can be copolymerized, or a compound represented
by general formula (I) and a compound not represented by general
formula (I) can be copolymerized. The compound that can be used for
copolymerization with a compound represented by general formula (I)
is not specifically limited and can be suitably selected based on
the objective. Examples include (meth)acrylic acid esters,
(meth)acrylamides, vinyl ethers, and styrenes (for example, styrene
and styrene derivatives).
[0049] Examples of the above (meth)acrylic acid esters include
methyl(meth)acrylate, ethyl(meth)acrylate, n-propyl(meth)acrylate,
isopropyl(meth)acrylate, n-butyl(meth)acrylate,
isobutyl(meth)acrylate, t-butyl(meth)acrylate,
n-hexyl(meth)acrylate, cyclohexyl(meth)acrylate,
t-butylcyclohexyl(meth)acrylate, 2-ethylhexyl(meth)acrylate,
t-octyl(meth)acrylate, dodecyl(meth)acrylate,
hexadecyl(meth)acrylate, pentadecyl(meth)acrylate,
octadecyl(meth)acrylate, acetoxyethyl(meth)acrylate,
phenyl(meth)acrylate, 2-methoxyethyl(meth)acrylate,
2-ethoxyethyl(meth)acrylate, 2-(2-metoxyethoxy)ethyl(meth)acrylate,
benzyl(meth)acrylate, diethyleneglycol
monomethylether(meth)acrylate, diethyleneglycol
monoethylether(meth)acrylate, diethyleneglycol
monophenylether(meth)acrylate, trimethyleneglycol
monomethylether(meth)acrylate, triethyleneglycol
monoethylether(meth)acrylate, polyethyleneglycol
monomethylether(meth)acrylate, polyethyleneglycol
monoethylether(meth)acrylate, beta-phenoxyethoxyethyl acrylate,
nonylphenoxypolyethyleneglycol(meth)acrylate,
dicyclopentanyl(meth)acrylate, dicyclopentenyl(meth)acrylate,
dicyclopentyloxyethyl(meth)acrylate, trifluoroethyl(meth)acrylate,
octafluoropentyl(meth)acrylate, perfluorooctylethyl(meth)acrylate,
tribromophenyl(meth)acrylate, and
tribromophenyloxyethyl(meth)acrylate.
[0050] Examples of the above (meth)acrylamides include
(meth)acrylamide, N-methyl meth(acrylamide),
N-ethyl(meth)acrylamide, N-propyl(meth)acrylamide,
N-isopropyl(meth)acrylamide, N-n-butyl(meth)acrylamide,
N-t-butyl(meth)acrylamide, N-cyclohexyl(meth)acrylamide,
N-(2-methoxyethyl)(meth)acrylamide, N,N-dimethyl(meth)acrylamide,
N,N-diethyl(meth)acrylamide, N-phenyl(meth)acrylamide,
N-benzyl(meth)acrylamide, (meth)acryloylmorpholine, and diacetone
acrylamide.
[0051] Examples of the above styrenes include styrene and styrene
derivatives (such as methylstyrene, dimethylstyrene,
trimethylstyrene, ethylstyrene, isopropylstyrene, butylstyrene,
methoxystyrene, butoxystyrene, acetoxystyrene, chlorostyrene,
dichlorostyrene, bromostyrene, hydroxystyrene protected by groups
(such as t-Boc) that can be removed by an acidic substance, vinyl
methylbenzoate, and alpha-methylstyrene).
[0052] Examples of the above vinyl ethers include methyl vinyl
ether, butyl vinyl ether, hexyl vinyl ether, and methoxyethyl vinyl
ether.
[0053] The molar ratio of the compound represented by general
formula (I) to the compound not represented by general formula (I)
during copolymerization is preferably 100:0 to 20:80, more
preferably 100:0 to 30:70, and further preferably, 100:0 to
50:50.
[0054] The molecular weight of the polymer obtained by polymerizing
the compound represented by general formula (I) is not specifically
limited, but is preferably 1,000 to 100,000.
[0055] Examples of polymers obtained by polymerizing the compound
represented by general formula (I) include polymers containing the
structural unit represented by general formula (11) below:
##STR00013##
(wherein R.sup.11 represents hydrogen atom or methyl group and
R.sup.1 represents a hydrogen atom or a substituted or
unsubstituted alkyl group) and polymers containing the structural
unit represented by general formula (12) below:
##STR00014##
(wherein R.sup.12 represents hydrogen atom or methyl group and Phe
represents an iodine-substituted phenyl group having two or more
iodine atoms, with the iodine-substituted phenyl group being
optionally substituted with a substituent selected from the group
consisting of amino group, carboxyl group, a halogen atom,
--NR.sup.3(C.dbd.O)R.sup.4, --(C.dbd.O)OR.sup.5,
--(C.dbd.O)NR.sup.6R.sup.7 (with each of R.sup.3 to R.sup.7
representing an alkyl group or an aryl group), an alkyl group, and
an aryl group).
[0056] A polymer containing both the structural unit represented by
general formula (11) and the structural unit represented by general
formula (12) is also preferable. The molar ratio of these
structural units (general formula (11): general formula (12)) is
preferably 0:100 to 50:50, more preferably 0:100 to 40:60, and
further preferably, 0:100 to 30:70.
[0057] Particles can be formed in an aqueous solution of the
polymer obtained by polymerizing the compound represented by
general formula (I) prepared as set forth above. The diameter of
the particles is preferably 4 to 400 nm, more preferably 4 to 200
nm.
[0058] Such polymer particles can be employed as imaging agents,
for example. By way of example, an X-ray imaging agent can be
prepared with polymer particles produced using the compound
represented by general formula (I) containing iodine.
[0059] An imaging agent of high biocompatibility can be prepared by
forming polymer particles with compounds having an imaging effect,
for example. A paramagnetic metal compound is an example of a
compound having an imaging effect. Within the particle, the
compound having an imaging effect can be enveloped in the above
polymer, or the component having an imaging effect can form the
membrane of the particle with the polymer.
[0060] A tumor-selective imaging agent can be provided by linking
an antibody, such as an antibody to a protein that is overexpressed
at tumor sites, to the surface of the polymer particle. The polymer
particle of the present invention is of small diameter and can be
used to prepare an imaging agent that is resistant to capture by
the reticuloendothelial system.
EXAMPLES
[0061] The present invention is described in greater detail below
through examples. However, the scope of the present invention is
not limited to the examples given below.
Example 1
[0062] To a reaction vessel were charged glycidyl methacrylate
(made by Tokyo Chemical Industry Co., Ltd.) (3 weight parts),
dodecanoic acid (made by Tokyo Chemical Industry Co., Ltd.) (4.3
weight parts), tetrabutylammonium bromide (made by Wako Pure
Chemical Industries, Ltd.) (0.7 weight part), and dimethylacetamide
(made by Wako Pure Chemical Industries, Ltd.) (50 weight parts).
The mixture obtained was heated to 90.degree. C. in an oil bath and
stirred for 2 hours. Subsequently, 300 weight parts of water and 80
weight parts of ethyl acetate (made by Wako Pure Chemical
Industries, Ltd.) were added, and the solution was separated. The
organic solvent layer was washed with 200 weight parts of saturated
brine and then dried with magnesium sulfate. The magnesium sulfate
was removed by filtration, and the organic solvent was distilled
off under vacuum. The crude product obtained was purified by silica
gel chromatography, yielding 5.4 weight parts (a yield of 75
percent) of an oily intermediate 1A.
[0063] Next, oily intermediate 1A (4 weight parts), triethylamine
(made by Wako Pure Chemical Industries, Ltd.) (1.5 weight parts),
and methylene chloride (made by Wako Pure Chemical Industries,
Ltd.) (30 weight parts) were added to a separate reaction vessel
that had been cooled to -20.degree. C. in a nitrogen atmosphere. To
the mixture obtained were added through a dropping funnel 2.1
weight parts of 2-chloro-2-oxo-1,3,2-dioxaphospholane (CAS
6609-64-9) (made by Wako Pure Chemical Industries, Ltd.). The
mixture was stirred for 2 hours and then filtered to remove the
white crystals that had been produced. The solvent was removed by
vacuum distillation. The residue was charged to a reaction vessel.
Acetonitrile (made by Wako Pure Chemical Industries, Ltd.) (30
weight parts) and trimethylamine (made by Aldrich Chemical Co.) (3
weight parts) were added and the mixture was stirred for 24 hours
at 60.degree. C. After completion of the reaction, the reaction
solution was filtered to remove the solid material, and the solvent
was distilled off under vacuum. The crude product obtained was
purified by reverse phase silica gel chromatography, yielding 1.8
weight parts of Specific Compound Example 2 (a yield of 30
percent).
[0064] .sup.1H-NMR(300 MHz)CDCl.sub.3 6.11 (s, 1H), 5.58 (s, 1H),
4.65-4.50 (m, 1H), 4.40-4.24 (m, 6H), 3.75 (s, 2H), 3.35 (s, 9H),
2.30 (t, 2H), 1.91 (s, 3H), 1.60 (t, 2H), 1.35-1.20 (m, 16H), 0.89
(t, 3H)
Example 2
[0065] To a reaction vessel were charged glycidyl methacrylate
(made by Tokyo Chemical Industry Co., Ltd.) (3 weight parts),
palmitic acid (made by Tokyo Chemical Industry Co., Ltd.) (5.4
weight parts), tetrabutylammonium bromide (made by Wake Pure
Chemical Industries, Ltd.) (0.7 weight part), and dimethylacetamide
(made by Wake Pure Chemical Industries, Ltd.) (50 weight parts).
The mixture obtained was heated to 90.degree. C. in an oil bath and
stirred for 2 hours. Subsequently, water (300 weight parts) and
ethyl acetate (made by Wake Pure Chemical Industries, Ltd.) (80
weight parts) were added and the solution was separated. The
organic solvent layer was washed with saturated brine (200 weight
parts) and dried with magnesium sulfate. The magnesium sulfate was
removed by filtration and the organic solvent was distilled off
under vacuum. The crude product obtained was purified by silica gel
chromatography, yielding 4.6 weight parts (a yield of 55 percent)
of an oily intermediate 2A.
[0066] Next, oily intermediate 2A (4 weight parts), triethylamine
(made by Wake Pure Chemical Industries, Ltd.) (1.1 weight parts),
and methylene chloride (made by Wake Pure Chemical Industries,
Ltd.) (15 weight parts) were added to a separate reaction vessel
that had been cooled to -20.degree. C. in a nitrogen atmosphere. To
the mixture obtained was added
2-chloro-2-oxo-1,3,2-dioxaphospholane (CAS 6609-64-9) (made by Wako
Pure Chemical Industries, Ltd.) (1.5 weight parts) through a
dropping funnel. The mixture was stirred for 2 hours and then
filtered to remove the white crystals that had been produced. The
solvent was removed by vacuum distillation. The residue was charged
to a reaction vessel. Acetonitrile (made by Wake Pure Chemical
Industries, Ltd.) (30 weight parts) and trimethylamine (made by
Aldrich Chemical Co.) (3 weight parts) were added and the mixture
was stirred for 24 hours at 60.degree. C. After completion of the
reaction, the reaction solution was filtered to remove the solid
material, and the solvent was distilled off under vacuum. The crude
product obtained was purified by reverse phase silica gel
chromatography, yielding 3.8 weight parts of Specific Compound
Example 3 (a yield of 67 percent).
[0067] .sup.1H-NMR (300 MHz) CDCl.sub.3 6.11 (s, 1H), 5.58 (s, 1H),
4.65-4.50 (m, 1H), 4.40-4.24 (m, 6H), 3.75 (s, 2H), 3.35 (s, 9H),
2.30 (t, 2H), 1.91 (s, 3H), 1.60 (t, 2H), 1.35-1.20 (m, 24H), 0.89
(t, 3H)
Example 3
[0068] To a reaction vessel were charged glycidyl methacrylate
(made by Tokyo Chemical Industry Co., Ltd.) (3 weight parts),
2,3,5-triiodobenzoic acid (made by Tokyo Chemical Industry Co.,
Ltd.) (10.6 weight parts), tetrabutylammonium bromide (made by Wake
Pure Chemical Industries, Ltd.) (0.7 weight part), and
dimethylacetamide (made by Wake Pure Chemical Industries, Ltd.) (50
weight parts). The mixture obtained was heated to 90.degree. C. in
an oil bath and stirred for 2 hours. Subsequently, water (300
weight parts) and ethyl acetate (made by Wake Pure Chemical
Industries, Ltd.) (80 weight parts) were added and the solution was
separated. The organic solvent layer was washed with saturated
brine (200 weight parts) and dried with magnesium sulfate. The
magnesium sulfate was removed by filtration and the organic solvent
was distilled off under vacuum. The crude product obtained was
purified by silica gel chromatography, yielding 10.9 weight parts
(a yield of 80 percent) of an oily intermediate 3A.
[0069] Next, oily intermediate 3A (8 weight parts), triethylamine
(made by Wako Pure Chemical Industries, Ltd.) (1.3 weight parts),
and methylene chloride (made by Wako Pure Chemical Industries,
Ltd.) (30 weight parts) were added to a separate reaction vessel
that had been cooled to -20.degree. C. in a nitrogen atmosphere. To
the mixture obtained was added
2-chloro-2-oxo-1,3,2-dioxaphospholane (CAS 6609-64-9) (made by Wako
Pure Chemical Industries, Ltd.) (1.8 weight parts) through a
dropping funnel. The mixture was stirred for 2 hours and then
filtered to remove the white crystals that had been produced. The
solvent was removed by vacuum distillation. The residue was charged
to a reaction vessel. Acetonitrile (made by Wako Pure Chemical
Industries, Ltd.) (30 weight parts) and trimethylamine (made by
Aldrich Chemical Co.) (3 weight parts) were added to the reaction
vessel and the mixture was stirred for 24 hours at 60.degree. C.
After completion of the reaction, the reaction solution was
filtered to remove the solid material, and the solvent was
distilled off under vacuum. The crude product obtained was purified
by reverse phase silica gel chromatography, yielding 6.5 weight
parts of Specific Compound Example 28 (a yield of 65 percent).
[0070] .sup.1H-NMR (300 MHz) CDCl.sub.3 8.25 (s, 1H), 7.76 (s, 1H),
6.11 (s, 1H), 5.58 (s, 1H), 4.75-4.28 (m, 7H), 3.75 (s, 2H), 3.30
(s, 9H), 1.91 (s, 3H)
Example 4
[0071] To a reaction vessel were charged glycidyl methacrylate
(made by Tokyo Chemical Industry Co., Ltd.) (3 weight parts),
acetrizoic acid (CAS-85-36-9) (made by Tokyo Chemical Industry Co.,
Ltd.) (11.8 weight parts), tetrabutylammonium bromide (made by Wako
Pure Chemical Industries, Ltd.) (0.7 weight part), and
dimethylacetamide (made by Wako Pure Chemical Industries, Ltd.) (50
weight parts). The mixture obtained was heated to 90.degree. C. in
an oil bath and stirred for 2 hours. Subsequently, water (300
weight parts) and ethyl acetate (made by Wake Pure Chemical
Industries, Ltd.) (80 weight parts) were added and the solution was
separated. The organic solvent layer was washed with saturated
brine (200 weight parts) and dried with magnesium sulfate. The
magnesium sulfate was removed by filtration and the organic solvent
was distilled off under vacuum. The crude product obtained was
purified by silica gel chromatography, yielding 9.4 weight parts (a
yield of 64 percent) of an oily intermediate 4A.
[0072] Next, oily intermediate 4A (6 weight parts), triethylamine
(made by Wako Pure Chemical Industries, Ltd.) (0.9 weight part),
and methylene chloride (made by Wake Pure Chemical Industries,
Ltd.) (30 weight parts) were added to a separate reaction vessel
that had been cooled to -20.degree. C. in a nitrogen atmosphere. To
the mixture obtained was added
2-chloro-2-oxo-1,3,2-dioxaphospholane (CAS 6609-64-9) (made by Wake
Pure Chemical Industries, Ltd.) (1.4 weight parts) through a
dropping funnel. The mixture was stirred for 2 hours and then
filtered to remove the white crystals that had been produced. The
solvent was removed by vacuum distillation. The product obtained
was charged to a reaction vessel. Acetonitrile (made by Wako Pure
Chemical Industries, Ltd.) (30 weight parts) and trimethylamine
(made by Aldrich Chemical Co.) (3 weight parts) were added to the
reaction vessel and the mixture was stirred for 24 hours at
60.degree. C. After completion of the reaction, the reaction
solution was filtered to remove the solid material, and the solvent
was distilled off under vacuum. The crude product obtained was
purified by reverse phase silica gel chromatography, yielding 3.8
weight parts of Specific Compound Example 32 (a yield of 50
percent).
[0073] .sup.1H-NMR (300 MHz) CDCl.sub.3 8.25 (s, 1H), 7.90 (br,
1H), 6.11 (s, 1H), 5.58 (s, 1H), 4.75-4.28 (m, 7H), 3.75 (s, 2H),
2.17 (s, 3H), 1.91 (s, 3H)
Example 5
[0074] To a reaction vessel were charged Specific Compound Example
3 (3 weight parts), stearyl methacrylate (made by Tokyo Chemical
Industry Co., Ltd.) (1.8 weight parts), n-propanol (made by Wako
Pure Chemical Industries, Ltd.) (2 weight parts), and V-601 (made
by Wako Pure Chemical Industries, Ltd.) (0.002 weight part). Under
a nitrogen atmosphere, stirring was conducted for 8 hours at an
internal temperature of 80.degree. C. After completion of the
reaction, the reaction solution was slowly introduced into acetone
(100 weight parts), yielding 2.6 weight parts of a white solid.
[0075] A 0.1 weight part of the white solid was dissolved in 0.4
weight part of n-propanol (made by Wako Pure Chemical Industries,
Ltd.) and heated to 60.degree. C. A 1.6 weight part quantity of
pure water was added to the solution. Subsequently, the mixture was
stirred for 20 minutes, yielding a polymer particle dispersion. The
mean particle size of the polymer particles present in the
dispersion was 153 nm as measured with a particle diameter
measuring device (UPA-EX150 made by Nikkiso Co., Ltd.).
Example 6
[0076] To a reaction vessel were charged Specific Compound Example
28 (0.025 weight part), n-propanol (Wako Pure Chemical Industries,
Ltd.) (0.5 weight part), pure water (9.5 weight parts), and V-601
(made by Wako Pure Chemical Industries, Ltd.) (0.002 weight part).
Under a nitrogen atmosphere, stirring was conducted for 8 hours at
an internal temperature of 80.degree. C. The reaction solution
obtained was filtered through a gel (PD-10 columns: made by GE
Healthcare), yielding a polymer particle dispersion. The mean
particle size of the polymer particles present in the dispersion
was 101 nm as measured with a particle diameter measuring device
(UPA-EX150 made by Nikkiso Co., Ltd.).
EFFECT OF THE INVENTION
[0077] The present invention provides a new polymeric compound that
is useful for manufacturing hydrophilic polymer materials of high
biocompatibility.
* * * * *